Inflammation can be defined as an immunologic response to injury or irritation, characterized by local mobilization of white blood cells and antibodies, swelling, and fluid accumulation. This is a response that is identical whether the injurious agent is a pathogenic organism, foreign body, ischemia, physical trauma, ionizing radiation, electrical energy or extremes of temperature. Although a defense and repair mechanism of the body, the reactions produced during inflammation may be harmful and develop into e.g. chronic inflammation, hypersensitivity reactions, systemic or local inflammatory diseases. An inflammatory disease is in this context defined as a disease characterized by inflammation. Examples include, but are not limited to, allergic conditions, asthma, allergic rhinitis, inflammatory bowel disease (Crohn's disease and related conditions), multiple sclerosis, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, and cardiovascular diseases with an inflammatory component.
Allergy is a complex process in which environmental antigens induce clinically adverse reactions.
Asthma can be understood as a basically allergic disease of the lung and its tissues. The asthma inducing antigens, called allergens, typically elicit a specific IgE response and, although in most cases the allergens themselves have little or no intrinsic toxicity, they induce pathology when the IgE response in turn elicits an IgE-dependent or T cell-dependent hypersensitivity reaction.
Hypersensitivity reactions can be local or systemic and typically occur within minutes after allergen exposure in individuals who have previously been sensitized to the respective allergen.
The hypersensitivity reaction of allergy develops when the allergen is recognized by IgE antibodies bound to specific receptors on the surface of effector cells, such as mast cells, basophils, or eosinophils, which cause the activation of the effector cells and the release of mediators that produce the acute signs and symptoms of the reactions. Allergic diseases include asthma, allergic rhinitis (hay fever), atopic dermatitis, and anaphylaxis.
Asthma is thought to arise as a result of interactions between multiple genetic and environmental factors and is characterized by three major features: 1) intermittent and reversible airway obstruction caused by bronchoconstriction, increased mucus production, and thickening of the walls of the airways that leads to a narrowing of the airways, 2) airway hyperresponsiveness, and 3) airway inflammation. Certain cells are critical to the inflammatory reaction of asthma and they include T cells and antigen presenting cells, B cells that produce IgE, and mast cells, basophils, eosinophils, and other cells that bind IgE. These effector cells accumulate at the site of allergic reaction in the airways and release toxic products that contribute to the acute pathology and eventually to tissue destruction related to the disorder. Other resident cells, such as smooth muscle cells, lung epithelial cells, mucus-producing cells, and nerve cells may also be abnormal in individuals with asthma and may contribute to its pathology. While the airway obstruction of asthma, presenting clinically as an intermittent wheeze and shortness of breath, is generally the most pressing symptom of the disease requiring immediate treatment, the inflammation and tissue destruction associated with the disease can lead to irreversible changes that eventually makes asthma a chronic and disabling disorder requiring long-term management.
Chronic obstructive pulmonary (or airways) disease (COPD) is a condition defined physiologically as airflow obstruction that generally results from a mixture of emphysema and peripheral airway obstruction due to chronic bronchitis. Emphysema is characterized by destruction of alveolar walls leading to abnormal enlargement of the air spaces of the lung. Chronic bronchitis is defined clinically as the presence of chronic productive cough for three months in each of two successive years In COPD, airflow obstruction is usually progressive and is only partially reversible. By far the most important risk factor for development of COPD is cigarette smoking, although the disease does also occur in non-smokers.
Chronic inflammation of the airways is a key pathological feature of COPD. The inflammatory cell population comprises increased numbers of macrophages, neutrophils and CD8+ lymphocytes.
Inhaled irritants such as cigarette smoke activate macrophages resident in the respiratory tract as well as epithelial cells leading to release of chemokines (e. g., interleukin-8) and other chemotactic factors which act to increase the neutrophil/monocyte trafficking from the blood into lung tissue, and airways. Neutrophils and monocytes recruited into the airways can release a variety of potentially damaging mediators such as proteolytic enzymes and reactive oxygen species. Matrix degradation and emphysema, with airway wall thickening, surfactant dysfunction and mucus hypersecretion are all potential sequelae of this inflammatory response that lead to impaired airflow and gas exchange.
In both asthma and COPD, although resident cells of the lungs play important parts in disease induction, the movement of inflammatory cells into respiratory tissues can be considered a prerequisite for the late-phase and chronic pathologies of these diseases. Members of the PP2C family of serine/threonine protein phosphotases have recently been shown to be important in the intracellular signalling pathways related to the reorganization of the actin cytoskeleton and cell mobility (Koh et al., Current Biology 12,317-321, 2002).
In patients with active inflammatory bowel disease (IBD), the objective is to achieve clinical remission. For ulcerative colitis (UC), oral or rectal aminosalicylates are widely used, and in more severe flares, corticoids and occasionally cyclosporine. In active Crohn's disease, corticosteroids represent the main treatment; budesonide being one of the most preferred, as this steroid is better tolerated than prednisone. However, failure to respond, acutely or chronically, to glucocorticoid therapy is a common indication for surgery in IBD, with as many as 50% of patients with Crohn's disease (CD) and approximately 20% of patients with ulcerative colitis (UC) requiring surgery in their lifetime as a result of poor response to glucocorticoids. In clinical practice, patients refractory or intolerant to steroids, immunomodulators such as for example infliximab (Remicade®), can be considered.
Asthma is usually easy to manage and inhaled corticosteroids are the most effective medications currently available to treat symptomatic asthma. However, approximately 5% of asthma patients are not controlled even on high doses of inhaled corticosteroids. Difficult therapy-resistant asthma may be defined as poorly controlled asthma in terms of chronic symptoms, episodic exacerbations, persistent and variable airways obstruction despite the use of high doses of inhaled steroids. Consequently, the disease management of asthma—in particular severe and steroid-resistant asthma—remains a real and daily challenge in the clinic.
Nevertheless, considerable progress has been made in development of drugs for asthma. There have however been few advances in the treatment of other bronchial inflammatory disorders such as chronic obstructive pulmonary disease (COPD). New therapeutic approaches to prevent disease progression are urgently needed, as the inflammatory response in COPD is essentially steroid-resistant.
As with the previously mentioned inflammatory diseases, a proportion of rheumatoid arthritis (RA) patients do not respond adequately to corticosteroids therapy. Likewise, as seen with the other indications, RA patients can be divided on clinical grounds into corticosteroid sensitive (CS) and corticosteroid resistant (CR) subgroups. The underlying mechanism involved in the CS and CR phenomena in patients with RA remain unknown but are of considerable therapeutic interest.
Overall there is an obvious need to address the need of patients that appear unresponsive to conventional steroid therapies or indeed are treatment resistant to a more general spectrum of medications.
Further aims underlying the invention, as well as their associated solutions, will become apparent upon study of the present description, examples and claims.